1. Field of the Invention
The invention relates to compounds, pharmaceutical compositions, and methods for treating or alleviating the symptoms of inflammation such as, for example, asthma.
2. Summary of the Related Art
Inflammation is a multi-focal host response to cellular or vascular tissue damage. Examples of diseases with an associated inflammatory reaction run the gamut from leprosy, asthma or pneumonia to rheumatoid arthritis or tuberculosis. (Trowbridge and Emling, “Inflammation: A Review of the Process” Quintessence Pub. Co. 1997).
Recent non-specific anti-inflammatory therapies have been directed at blocking the inflammatory reaction at distinct points within the reaction cascade. Specific points of attack have included a) modulating the complement system; b) inhibiting soluble mediator release by mast cells or other reactive cells; c) inhibiting the influx of immunoreactive cells into the inflammatory site; d) blocking the adherence of the reactive cells to vessel walls; and e) prevent the extravascularization efflux of the immunoreactive cells into the damaged area. (See Trowbridge and Emling, supra; Ryan and Majno, Am. J. Pathol. 86:183–276, 1977); and Liles and Van Voohis, J. Infect. Dis. 172:1574–1580, 1995).
Asthma is a chronic disease of the large and small airways of the lung that affects 5% to 10% of the human population (Plaut and Zimmerman, “Allergy and Mechanisms of Hypersensitivity” in Fundamental Immunology, 3rd Ed., W. E. Paul (ed.), Raven Press, New York, N.Y. 1993, pp. 1399–1425). It is the most common chronic disease of childhood and the leading cause of school absence. Asthma in adults results in an estimated 27 million patient visits, 6 million lost workdays, and 90.5 million days of restricted activity per year. The morbidity and mortality rates for asthma are growing worldwide. For a general review of asthma see Sheffer et al., The National Asthma Education Program: Expert panel report guidelines for the diagnosis and management of asthma, Med. Care 31:MS20, 1993. In addition to humans, asthmatic reactions are a growing problem for some animals e.g., the horse racing industry is affected by horses that suffer from asthmatic reactions.
The most prominent characteristic of asthma is bronchospasm, or narrowing of the airways; asthmatic patients have prominent contraction of the smooth muscles of large and small airways, increased mucus production, and increased inflammation (Plaut and Zimmerman, supra). Hogg teaches that the inflammatory response in asthma is typical for tissues covered by a mucosa and is characterized by vasodilation, plasma exudation, recruitment of inflammatory cells such as neutrophils, monocytes, macrophages, lymphocytes, and eosinophils to the sites of inflammation, and the release of inflammatory mediators by resident tissue cells (eg, mast cells) or by tin inflammatory cells (Hogg, “Pathology of Asthma,” in Asthma as an Inflammatory Disease, O'Byrne (ed.), Marcel Dekker, Inc., New York;, N.Y. 1990, pp. 1–13).
Hargreave et al. teach that asthma may be triggered by a variety of causes such as allergic reactions, a secondary response to infections, industrial or occupational exposures, ingestion of certain chemicals or drugs, exercise, and vasculitis (Hargreave et al., J. Allergy Clinical Immunol. 83:1013–1026,1986). In many cases, there are two phases to an allergic asthma attack, an early phase and a late phase which follows 4–6 hours after bronchial stimulation (Harrison's Principles of Internal Medicine, 14th Ed., Fauci et al. (eds), McGraw-Hill, New York, N.Y. 1998, pp. 1419–1426). The early phase, which resolves spontaneously, includes the immediate inflammatory response including the reactions caused by the release of cellular mediators from mast cells. The late phase reactions develop over a period of hours and are characterized histologically by an early influx of polymorphonuclear leukocytes and fibrin deposition followed later by infiltration of eosinophils.
A number of allergic asthma patients ate “dual responders”, and develop bot an early (i.e., acute) and a late phase response. In dual responders, the acute response is followed 4–12 hours later by a secondary increase in airway resistance (“late phase response” or LPR). Late responses and, thus, dual responders are of clinical importance, because, in combination with airway inflammation, late phase responses lead to prolonged airway hyperreactivity (AHR), asthmatic exacerbations, or hyperresponsiveness, worsen of symptoms, and generally a more severe form of clinical asthma that may last from days to months in some subjects, requiring aggressive therapy. Pharmacological studies in allergic animals have demonstrated that not only the bronchoconstrictor response but also the inflammatory cell influx and the mediator release pattern in dual responders is quite different from acute responders.
An increase in bronchial hyperreactivity (AHR), the hallmark of a more severe orm of asthma can be induced by both antigenic and non-antigenic stimuli. Late phase response allergen-induced asthma and persistent hyperresponsiveness have been associated with the recruitment of leukocytes, and particularly eosinophils, to inflamed lung issue (Abraham et al., Arm Rev. Respir. Dis. 138:1565–157, 1988). Eosinophils release several inflammatory mediators including 15-HETE, leukotriene C4, PAF, cationic proteins, eosinophil peroxidase.
It should be noted, however, that the airways are merely a prototype of organs or tissues affected by late phase reactions (LPR's). The late phase bronchoconstriction and airway hyperreactivity (AHR) observed in dual responder asthmatic patients is not an isolated phenomenon restricted to asthmatic or even pulmonary conditions. There are cutaneous, nasal, ocular and systemic manifestations of LPR's in addition to the pulmonary ones. According to the latest understanding of LPR mechanisms, it appears that the clinical diseases (whether of the skin, lung, nose, eye, or other organs) recognized to involve allergic mechanisms have a histologic inflammatory component which follows the immediate allergic or hypersensitivity reaction that occurs on antigen challenge. This response sequence appears to be connected to mast cell mediators and propagated by other resident cells within target organs or by cells recruited into the sites of mast cell or basophilic degranulation.
Conventional anti-asthma treatments have been predicated on the strict avoidance of all allergens, which is inherently difficult to achieve, and on therapeutic regimens based on pharmacological agents having unfortunate side effects and suboptimal pharmacokinetic properties.
For example, commonly used anti-asthma therapeutics, β2-adrenergic agonists, are potent agents for the treatment of bronchospasm, but have no effect on airway inflammation or bronchial hyperreactivity. Thus, Palmer et al. describe the introduction of salmeterol, a long-acting β2-adrenergic agonist, as an adjunct to anti-inflammatory therapy in asthma management (Paler et al., New Engl. J. Med. 331:1314–1319, 1994). However, Bhagat et al. allege that regular or prolonged use of β2-adrenergic adrenergic agonists is associated with poor control of asthma, increase in airway hyperresponsiveness to allergen, and reduced protection against bronchoconstriction induced by exercise, histamine, methacholine and allergens challenge (Bhagat etal Chest 108:1235–1238, 1995). Moreover, chronic use of β2radrenergic agents alone, by causing down regulation of β2 -adrenergic receptors, is suspected to worsen bronchial hyperreactivity.
Another often-prescribed anti-asthma agent, theophylline (a methylxanthine), is characterized by substantial variability in its absorbance and clearance. Woolock et al. describe the use of corticosteroids to treat late-phase and airway hyperactivity reactions, reporting that, while relatively safe in adult patients with asthma, inhaled corticosteroids have tremendous toxicity in children, including adrenal suppression and reduced bone density and growth (Woolock et al, Am. Respir. Crit. Care Med. 153:1481–1488, 1996). Volcheck et al. describe the use of cromolyn to prevent both the early and late phases of asthma inflammatory reactions. Comolyn however, has been found to be effective in preventing the onset of an asthma reaction only if given prior to an astma attack (Volcheck et al, Postgrad Med. 104(3):127–136, 1998).
Antihustamines occasionally prevent or abort allergic asthmatic episodes, particularly in children, but they can only be partially effective in asthma because histamine is only one of many mediators (Cuss, “The Pharmacology of Antiasthma Medications,” in Asthma as an Inflammatory Diease, O'Byrne, ed. (Marcel Dekker, Inc.; New York 1990, pp. 199–250) and O'Byme, “Airway Inflammation and and Asthma,” in Asthma as Inflammatory Disease, O'Byrne (ed.), Marcel Dekker, Inc., New York, N.Y. 1990, pp. 143–157).
Parish, et al, discloses in WO88/05301 naturally occurring sulfated polysaccharides believed to have anti-flammatory propertes, These include hyaluronic acid, chondroitin sulfate, fucoidan and carrageenan lamba as inhibitors or blocker of endoglycosylase actvty (e.g., heparinase). Simiar activity was also demonstrated by heparin or heparin derivatives such as periodate oxidized, reduced heparins.
Bioactive mediator substances such as histamine, heparin, TNF-α, LTB4, proteases and a host of cytokines released by reactive cells (e.g., mast cells) have been investigated as potentially useful anti-inflammatory agents or targets. (Goodman & Gilman's “The Pharmacological Basis of Tenrapeutics”, Hardman, et al., McGraw-Hill, 10th ed. pp. 734 (2001); Buetler & Cerami, Ann. Rev. Immunol. 7:625–55;(1989).
An underlying theory advocated by some is that by up or down regulating an intermediate compound within the cascade, one could conceivable fine-tune, suppress or even prevent the inflammatory response. Cohen, et al, (WO92/19249; U.S. Pat. No. 5,474,987; U.S. Pat. No. 5,686,431; U.S. Pat. No. 5,908,837) showed low molecular weight heparin (molecular weight between 3 kDa and 6 kDa) reducing TNF-α secretion. However, Cohen, et al., did not teach or suggest modification of low molecular weight heparn.
Subsequent work by iohen, et al., (see WO94/11006; U.S. Pat. No. 5,861,382; and U.S. Pat. No. 6,020,323) identified specific moieties postulated to have the ability of down megulating TNF-α secretion and thus potenally useful as anti-inflammatory compounds for some conditions. The core compounds reported by Cohen are 4 variants of an N-sulfated 4-deoxy-4en-iduronoglucosamine or N-acetylated 4-demly 4-en-iduronoglucosamine. Notably, of seven additional sulfation substitution variations examined, 6 were found to be “neutral” in their ability to suppress the activity of TNF-α while one siufation substitution variant actually augmented TNF-α activity.
The relationship between the degree of heparin sulfation and inflammation remains unsettled The prior art as a whole teaches away from the hypersulfation of the reactive moieties. Kennedy (U.S. Pat. No. 5,990,097), discloses that a seleely 2-O, 3-O-desulfated heparin was a potent inhibitor of airway smooth muscle proliferation, an event associated with pulmonary inflammation. Addinonally, Kilfeather, et at., (Brit. J. Phanracol, LA-1442–1446, 1995) teaches that where there is no modification to, or elmination of, the sulfate groups present, heparin or low molecular weight heparin is able to inhibit the in vitro serum induced proliferation of bovine tracheal smooth muscle cells. Kennedy and Kilfeather, et al., distinguishable from each other not only on the issue of sulfation but also bythe fact that Kilfeater additionally used low molecular weight heparin fragnents (MW>3 kDa) while Kennedy did not.
Where the prior art uses intact heparin (e.g., Kennedy) or low molecular weight hepann (Cohen), Ahmned (U.S. Pat. No. 5,690,910; and U.S. Pat. No. 5,980,865) teaches the use of ultra low molecular weight heparin with a molecular weight <3 kDa which is distinguishable from Cohen's >3 kDa molecular weight heparin fractions. Additionally, where Cohen teaches parenteral, oral or topical routes of administration for the low molecular heparin, Ahmed discloses that the ultra-low molecular weight heparins can also be administered by inhalation, intra-ocular, intra-nasal, or intra-bronchial routes. The issue of hypersulfation is not addressed except by Cohen's investigation at the disaccharide level of sulfate substitutions at only three sites of an N-sulfated 4-deoxy-4-en-iduronoglucosamine or N-acetylated 4-deoxy-4-en-iduronoglucosamine which showed limited success by generating only 4 active variants. Hence, there is a trend in the art emphasizing desulfation and moving away from hypersulfation.
Thus, the current drug modalities used for treatment of asthma suffer from a number of drawbacks. In general, the conventional agents have a relatively short duration of action and may be partially or wholly ineffective when administered after antigen challenge occurs. Moreover, because of serious adverse effects associated with the use of agents such as β2-adrenergic agonists and corticosteroids, the therapeutic margin of safety with such agents is relatively narrow and patients using them must be carefully monitored (WO 94/06783, WO 99/06025, U.S. Pat. No. 5,690,910, U.S. Pat. No. 5,980,865).
Therefore, there remains a need to identify and develop improved compositions and methods for treating or alleviating the symptoms of inflammation in inflammatory diseases which can include allergic reactions, asthma and asthnma-related pathologies. Such methods and compositions should address the shortcomings of traditional therapeutic approaches.